Structural diversity of g proteincoupled receptors and significance for drug discovery

Nature Reviews Drug Discovery

Volumn 7, Issue 4, 2008, Pages 339-357

  Schiöth, Helgi B ^a   Lagerström, Malin C ^a  

^a UPPSALA UNIVERSITY   (Sweden)

Author keywords

[No Author keywords available]

Indexed keywords

G PROTEIN COUPLED RECEPTOR; LIGAND;

ANIMAL; BINDING SITE; CHEMICAL STRUCTURE; CHEMISTRY; DRUG DESIGN; GENETICS; HUMAN; METABOLISM; PHYSIOLOGY; PROTEIN CONFORMATION; REVIEW;

ANIMALS; BINDING SITES; DRUG DESIGN; HUMANS; LIGANDS; MODELS, MOLECULAR; PROTEIN CONFORMATION; RECEPTORS, G-PROTEIN-COUPLED;

EID: 42149181885     PISSN: 14741776     EISSN: 14741784     Source Type: Journal    
DOI: 10.1038/nrd2518     Document Type: Article

References (253)

1. Nathans, J. & Hogness, D. S. Isolation, sequence analysis, and intron-exon arrangement of the gene encoding bovine rhodopsin. Cell 34, 807-814 (1983).
2. Hargrave, P. A. et al. The structure of bovine rhodopsin. Biophys. Struct. Mech. 9, 235-244 (1983).
3. Hargrave, P A. et al. Rhodopsin’s protein and carbohydrate structure: selected aspects. Vision Res. 24, 1487-1499 (1984).
4. Lefkowitz, R. J. Historical review: a brief history and personal retrospective of seven-transmembrane receptors. Trends Pharmacol. Sci. 25, 413-422 (2004).
5. Dixon, R. A. et al. Cloning of the gene and cDNA for mammalian ß-adrenergic receptor and homology with rhodopsin. Nature 321,75-79 (1986).
6. Kobilka, B. K. et al. Functional activity and regulation of human ß2-adrenergic receptors expressed in Xenopus oocytes. J. Biol. Chem. 262, 15796-15802 (1987).
7. Felder, C. C. et al. Anandamide, an endogenous cannabimimetic eicosanoid, binds to the cloned human cannabinoid receptor and stimulates receptor-mediated signal transduction. Proc. Natl Acad. Sci. USA 90, 7656-7660 (1993).
8. Masu, Y. et al. cDNA cloning of bovine substance-K receptor through oocyte expression system. Nature 329, 836-838 (1987).
9. Parmentier, M. et al. Molecular cloning of the thyrotropin receptor. Science 246, 1620-1622 (1989).
10. Attwood, T. K. & Findlay, J. B. Design of a discriminating fingerprint for G-protein-coupled receptors. Protein Eng. 6, 167-176 (1993).
11. Attwood, T. K. & Findlay, J. B. Fingerprinting G-protein-coupled receptors. Protein Eng. 7, 195-203 (1994).
12. Kolakowski, L. F. Jr. GCRDb: a G-protein-coupled receptor database. Receptors Channels 2, 1-7 (1994).
13. Foord, S. M. et al. International Union of Pharmacology. XLVI. G protein-coupled receptor list. Pharmacol. Rev. 57, 279-288 (2005).
14. Bockaert, J. & Pin, J. P Molecular tinkering of G protein-coupled receptors: an evolutionary success. EMBO J. 18, 1723-1729 (1999).
15. Lander, E. S. et al. Initial sequencing and analysis of the human genome. Nature 409, 860-921 (2001).
16. Venter, J. C. et al. The sequence of the human genome. Science 291, 1304-1351 (2001).
17. Vassilatis, D. K. et al. The G protein-coupled receptor repertoires of human and mouse. Proc. Natl Acad. Sci. USA 100, 4903-4908 (2003).
18. Fredriksson, R., Lagerstrom, M. C., Lundin, L. G. & Schioth, H. B. The G-protein-coupled receptors in the human genome form five main families. Phylogenetic analysis, paralogon groups, and fingerprints. Mol. Pharmacol. 63, 1256-1272 (2003).
19. Adler, E. et al. A novel family of mammalian taste receptors. Cell 100, 693-702 (2000).
20. Matsunami, H., Montmayeur, J. P. & Buck, L. B. A family of candidate taste receptors in human and mouse. Nature 404, 601-604 (2000).
21. Fredriksson, R. & Schioth, H. B. The repertoire of G-protein-coupled receptors in fully sequenced genomes. Mol. Pharmacol. 67, 1414-1425 (2005).
22. Gloriam, D. E., Fredriksson, R. & Schioth, H. B. The G protein-coupled receptor subset of the rat genome. BMC Genomics 8, 338-405 (2007).
23. Lagerstrom, M. C. et al. The G protein-coupled receptor subset of the chicken genome. PLoS Comput. Biol. 2, 54 (2006).
24. Palczewski, K. et al. Crystal structure of rhodopsin: a G protein-coupled receptor. Science 289, 739-745 (2000).
25. Schwartz, T. W. Locating ligand-binding sites in 7TM receptors by protein engineering. Curr. Opin. Biotechnol. 5, 434-444 (1994).
26. Frimurer, T. M. et al. A physicogenetic method to assign ligand-binding relationships between 7TM receptors. Bioorg. Med. Chem. Lett. 15, 3707-3712 (2005).
27. Cherezov, V. et al. High-resolution crystal structure of an engineered human ß2-adrenergic G protein coupled receptor. Science 318, 1258-1265 (2007).
28. Rasmussen, S. G. et al. Crystal structure of the human ß2 adrenergic G-protein-coupled receptor. Nature 450, 383-387 (2007).
29. Vu, T. K., Hung D. T., Wheaton, V. I. & Coughlin, S. R. Molecular cloning of a functional thrombin receptor reveals a novel proteolytic mechanism of receptor activation. Cell 64, 1057-1068 (1991).
30. Xu, W. F. et al. Cloning and characterization of human protease-activated receptor 4. Proc. Natl Acad. Sci. USA 95, 6642-6646 (1998).
31. Nystedt, S., Emilsson, K., Larsson, A. K., Strombeck, B. & Sundelin, J. Molecular cloning and functional expression of the gene encoding the human proteinase-activated receptor 2. Eur. J. Biochem. 232, 84-89 (1995).
32. Ishihara, H. et al. Protease-activated receptor 3 is a second thrombin receptor in humans. Nature 386, 502-506 (1997).
33. Oikonomopoulou, K. et al. Proteinase-mediated cell signalling: targeting proteinase-activated receptors (PARs) by kallikreins and more. Biol. Chem. 387, 677-685 (2006).
34. Hsu, S. Y. et al. The three subfamilies of leucine-rich repeat-containing G protein-coupled receptors (LGR): identification of LGR6 and LGR7 and the signaling mechanism for LGR7. Mol. Endocrinol. 14, 1257-1271 (2000).
35. Hsu, S. Y. et al. Activation of orphan receptors by the hormone relaxin. Science 295, 671-674 (2002).
36. Fan, Q. R. & Hendrickson, W. A. Structure of human follicle-stimulating hormone in complex with its receptor. Nature 433, 269-277 (2005).
37. Tyndall, J. D. & Sandilya, R. GPCR agonists and antagonists in the clinic. Med. Chem. 1,405-421 (2005).
38. Surgand, J. S., Rodrigo, J., Kellenberger, E. & Rognan, D. A chemogenomic analysis of the transmembrane binding cavity of human G-protein-coupled receptors. Proteins 62, 509-538 (2006).
39. Jacoby, E., Bouhelal, R., Gerspacher, M. & Seuwen, K. The 7 TM G-protein-coupled receptor target family. ChemMedChem 1, 761-782 (2006).
40. Strader, C. D., Sigal, I. S. & Dixon, R. A. Structural basis of ß-adrenergic receptor function. FASEB J. 3, 1825-1832 (1989).
41. Liapakis, G. et al. The forgotten serine. A critical role for Ser-2035.42 in ligand binding to and activation of the ß2-adrenergic receptor. J. Biol. Chem. 275, 377729-37788 (2000).
42. Swaminath, G. et al. Sequential binding of agonists to the ß2 adrenoceptor. Kinetic evidence for intermediate conformational states. J. Biol. Chem. 279, 686-69 (2004).
43. Van Gaal, L. F., Rissanen, A. M., Scheen, A. J., Ziegler, O. & Rossner, S. Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study. Lancet 365, 1389-1397 (2005).
44. Onuffer, J. J. & Horuk, R. Chemokines, chemokine receptors and small-molecule antagonists: recent developments. Trends Pharmacol. Sci. 23, 459-467 (2002).
45. Civelli, O., Saito, Y., Wang, Z., Nothacker, H. P. & Reinscheid, R. K. Orphan GPCRs and their ligands. Pharmacol. Ther. 110, 525-532 (2006).
46. Overton, H. A. et al. Deorphanization of a G proteincoupled receptor for oleoylethanolamide and its use in the discovery of small-molecule hypophagic agents. Cell. Metab. 3, 167-175 (2006).
47. Fredriksson, R., Hoglund, P. J., Gloriam, D. E., Lagerstrom, M. C. & Schioth, H. B. Seven evolutionarily conserved human rhodopsin G proteincoupled receptors lacking close relatives. FEBS Lett. 554, 381-388 (2003).
48. Hirasawa, A. et al. Free fatty acids regulate gut incretin glucagon-like peptide-1 secretion through GPR120. Nature Med. 11,90-94 (2005).
49. Thomas, P., Pang, Y., Filardo, E. J. & Dong, J. Identity of an estrogen membrane receptor coupled to a G protein in human breast cancer cells. Endocrinology 146, 624-632 (2005).
50. Wang, J. et al. Kynurenic acid as a ligand for orphan G protein-coupled receptor GPR35. J. Biol. Chem. 281, 22021-22028 (2006).
51. Tabata, K., Baba, K., Shiraishi, A., Ito, M. & Fujita, N. The orphan GPCR GPR87 was deorphanized and shown to be a lysophosphatidic acid receptor. Biochem. Biophys. Res. Commun. 363, 861-866 (2007).
52. Bjarnadottir, T. K. et al. Comprehensive repertoire and phylogenetic analysis of the G protein-coupled receptors in human and mouse. Genomics 88, 263-273 (2006).
53. Levoye, A. et al. The orphan GPR50 receptor specifically inhibits MT1 melatonin receptor function through heterodimerization. EMBO J. 25, 3012-3023 (2006).
54. Galvez, T. et al. Allosteric interactions between GB1 and GB2 subunits are required for optimal GABAB receptor function. EMBO J. 20, 2152-2159 (2001).
55. Jones, K. A. et al. GABAB receptors function as a heteromeric assembly of the subunits GABAbR 1 and GABAbR2. Nature 396, 674-679 (1998).
56. Robbins, M. J. et al. GABAb-, is essential for G-protein coupling of the GABAB receptor heterodimer. J. Neurosci. 21, 8043B-8052 (2001).
57. Hoon, M. A. et al. Putative mammalian taste receptors: a class of taste-specific GPCRs with distinct topographic selectivity. Cell 96, 541-551 (1999).
58. Li, X. et al. Human receptors for sweet and umami taste. Proc. Natl Acad. Sci. USA 99, 4692-4696 (2002).
59. Nelson, G. et al. An amino-acid taste receptor. Nature 416, 199-202 (2002).
60. Nelson, G. et al. Mammalian sweet taste receptors. Cell 106, 381-390 (2001).
61. Sainz, E., Korley, J. N., Battey, J. F. & Sullivan, S. L. Identification of a novel member of the T1R family of putative taste receptors. J. Neurochem. 77, 896-903 (2001).
62. Libert, F. et al. Selective amplification and cloning of four new members of the G protein-coupled receptor family. Science 244, 569-572 (1989).
63. Buck, L. & Axel, R. A novel multigene family may encode odorant receptors: a molecular basis for odor recognition. Cell 65, 175-187 (1991).
64. Parmentier, M. et al. Expression of members of the putative olfactory receptor gene family in mammalian germ cells. Nature 355, 453-455 (1992).
65. Mombaerts, P. The human repertoire of odorant receptor genes and pseudogenes. Annu. Rev. GenomicsHum. Genet. 2, 493-510 (2001).
66. Malnic, B., Godfrey, P. A. & Buck, L. B. The human olfactory receptor gene family. Proc. Natl Acad. Sci. USA 101, 2584-2589 (2004).
67. Niimura, Y. & Nei, M. Evolution of olfactory receptor genes in the human genome. Proc. Natl Acad. Sci. USA 100, 12235-12240 (2003).
68. Zozulya, S., Echeverri, F. & Nguyen, T. The human olfactory receptor repertoire. Genome Biol. 2, Research0018.1-0018.12 (2001).
69. Glusman, G. et al. The olfactory receptor gene superfamily: data mining, classification, and nomenclature. Mamm. Genome 11, 1016-1023 (2000).
70. Rovati, G. E., Capra, V. & Neubig, R. R. The highly conserved DRY motif of class A G protein-coupled receptors: beyond the ground state. Mol. Pharmacol. 71, 959-964 (2007).
71. Man, O., Gilad, Y. & Lancet, D. Prediction of the odorant binding site of olfactory receptor proteins by human-mouse comparisons. Protein Sci. 13, 240-254 (2004).
72. Floriano, W. B., Vaidehi, N., Goddard, W. A., Singer, M. S. & Shepherd, G. M. Molecular mechanisms underlying differential odor responses of a mouse olfactory receptor. Proc. Natl Acad. Sci. USA 97, 10712-10716 (2000).
73. Gaillard, I., Rouquier, S., Chavanieu, A., Mollard, P. & Giorgi, D. Amino-acid changes acquired during evolution by olfactory receptor 912-93 modify the specificity of odorant recognition. Hum. Mol. Genet. 13, 771-780 (2004).
74. Singer, M. S. Analysis of the molecular basis for octanal interactions in the expressed rat 17 olfactory receptor. Chem. Senses 25, 155-165 (2000).
75. Malnic, B., Hirono, J., Sato, T. & Buck, L. B. Combinatorial receptor codes for odors. Cell 96, 713-723 (1999).
76. Wetzel, C. H. et al. Specificity and sensitivity of a human olfactory receptor functionally expressed in human embryonic kidney 293 cells and Xenopus laevis oocytes. J. Neurosci. 19, 7426-7433 (1999).
77. Spehr, M. et al. Identification of a testicular odorant receptor mediating human sperm chemotaxis. Science 299, 2054-2058 (2003).
78. Shirokova, E. et al. Identification of specific ligands for orphan olfactory receptors. G protein-dependent agonism and antagonism of odorants. J. Biol. Chem. 280, 11807-11815 (2005).
79. Krautwurst, D., Yau, K. W. & Reed, R. R. Identification of ligands for olfactory receptors by functional expression of a receptor library. Cell 95, 917-926 (1998).
80. Matarazzo, V. et al. Functional characterization of two human olfactory receptors expressed in the baculovirus sf9 insect cell system. Chem. Senses 30, 195-207 (2005).
81. Young, J. M. & Trask, B. J. The sense of smell: genomics of vertebrate odorant receptors. Hum. Mol. Genet. 11, 1153-1160 (2002).
82. Harmar, A. J. Family-B G-protein-coupled receptors. Genome Biol. 2, Reviews3013.1-3113.10 (2001).
83. Ishihara, T. et al. Molecular cloning and expression of a cDNA encoding the secretin receptor. EMBO J. 10, 1635-1641 (1991).
84. Hofmann, B. A. et al. Functional and protein chemical characterization of the N-terminal domain of the rat corticotropin-releasing factor receptor 1. Protein Sci. 10, 2050-2062 (2001).
85. Grauschopf, U. et al. The N-terminal fragment of human parathyroid hormone receptor 1 constitutes a hormone binding domain and reveals a distinct disulfide pattern. Biochemistry 39, 8878-8887 (2000).
86. Bazarsuren, A. et al. In vitro folding, functional characterization, and disulfide pattern of the extracellular domain of human GLP-1 receptor. Biophys. Chem. 96, 305-318 (2002).
87. Grace, C. R. et al. NMR structure and peptide hormone binding site of the first extracellular domain of a type B1 G protein-coupled receptor. Proc. Natl Acad. Sci. USA 101, 12836-12841 (2004).
88. Godfrey, P. et al. GHRH receptor of little mice contains a missense mutation in the extracellular domain that disrupts receptor function. Nature Genet. 4, 227-232 (1993).
89. DeAlmeida, V. I. & Mayo, K. E. Identification of binding domains of the growth hormone-releasing hormone receptor by analysis of mutant and chimeric receptor proteins. Mol. Endocrinol. 12, 750-765 (1998).
90. Assil, I. Q., Qi, L. J., Arai, M., Shomali, M. & Abou- Samra, A. B. Juxtamembrane region of the amino terminus of the corticotropin releasing factor receptor type 1 is important for ligand interaction. Biochemistry 40, 1187-1195 (2001).
91. Vilardaga, J. P., Lin, I. & Nissenson, R. A. Analysis of parathyroid hormone (PTH)/secretin receptor chimeras differentiates the role of functional domains in the pth/ pth-related peptide (PTHrP) receptor on hormone binding and receptor activation. Mol. Endocrinol. 15, 1186-1199 (2001).
92. Unson, C. G. et al. Roles of specific extracellular domains of the glucagon receptor in ligand binding and signaling. Biochemistry 41, 11795-11803 (2002).
93. Pham, V., Wade, J. D., Purdue, B. W. & Sexton, P. M. Spatial proximity between a photolabile residue in position 19 of salmon calcitonin and the amino terminus of the human calcitonin receptor. J. Biol. Chem. 279, 6720-6729 (2004).
94. Dong, M. et al. Spatial approximation between two residues in the mid-region of secretin and the amino terminus of its receptor. Incorporation of seven sets of such constraints into a three-dimensional model of the agonist-bound secretin receptor. J. Biol. Chem. 278, 48300-48312 (2003).
95. Dong, M., Pinon, D. I., Cox, R. F. & Miller, L. J. Importance of the amino terminus in secretin family G protein-coupled receptors. Intrinsic photoaffinity labeling establishes initial docking constraints for the calcitonin receptor. J. Biol. Chem. 279, 1167-1175 (2004).
96. Dong, M., Li, Z., Pinon, D. I., Lybrand, T. P & Miller, L. J. Spatial approximation between the amino terminus of a peptide agonist and the top of the sixth transmembrane segment of the secretin receptor. J. Biol. Chem. 279, 2894-2903 (2004).
97. Nauck, M. A. & Meier, J. J. Glucagon-like peptide 1 and its derivatives in the treatment of diabetes. Regul. Pept. 128, 135-148 (2005).
98. Stacey, M., Lin, H. H., Gordon, S. & McKnight, A. J. LNB-TM7, a group of seven-transmembrane proteins related to family-B G-protein-coupled receptors. Trends Biochem. Sci. 25, 284-289 (2000).
99. Bjarnadottir, T. K. et al. The human and mouse repertoire of the adhesion family of G-protein-coupled receptors. Genomics 84, 23-33 (2004).
100. Baud, V. et al. EMR1, an unusual member in the family of hormone receptors with seven transmembrane segments. Genomics 26, 334-344 (1995).
101. Krasnoperov, V. G. et al. a-Latrotoxin stimulates exocytosis by the interaction with a neuronal G-protein-coupled receptor. Neuron 18, 925-937 (1995).
102. Krasnoperov, V. et al. Post-translational proteolytic processing of the calcium-independent receptor of a-latrotoxin (CIRL), a natural chimera of the cell adhesion protein and the G protein-coupled receptor. Role of the G protein-coupled receptor proteolysis site (GPS) motif. J. Biol. Chem. 277, 46518-46526 (2002).
103. Lin, H. H. et al. Autocatalytic cleavage of the EMR2 receptor occurs at a conserved G protein-coupled receptor proteolytic site motif. J. Biol. Chem. 279, 31823-31832 (2004).
104. Nechiporuk, T., Urness, L. D. & Keating, M. T. ETL, a novel seven-transmembrane receptor that is developmentally regulated in the heart. ETL is a member of the secretin family and belongs to the epidermal growth factor-seven-transmembrane subfamily. J. Biol. Chem. 276, 4150-4157 (2001).
105. Lin, H. H. et al. Molecular analysis of the epidermal growth factor-like short consensus repeat domainmediated protein-protein interactions: dissection of the CD97-CD55 complex. J. Biol. Chem. 276, 24160-24169 (2001).
106. Lelianova, V. G. et al. a-Latrotoxin receptor, latrophilin, is a novel member of the secretin family of G protein-coupled receptors. J. Biol. Chem. 272, 21504-21508 (1997).
107. Little, K. D., Hemler, M. E. & Stipp, C. S. Dynamic regulation of a GPCR-tetraspanin-G protein complex on intact cells: central role of CD81 in facilitating GPR56-Gaq/Il association. Mol. Biol. Cell 15, 2375-2387 (2004).
108. Stacey, M. et al. The epidermal growth factor-like domains of the human EMR2 receptor mediate cell attachment through chondroitin sulfate glycosaminoglycans. Blood 102, 2916-2924 (2003).
109. Stacey, M., Lin, H. H., Hilyard, K. L., Gordon, S. & McKnight, A. J. Human epidermal growth factor (EGF) module-containing mucin-like hormone receptor 3 is a new member of the EGF-TM7 family that recognizes a ligand on human macrophages and activated neutrophils. J. Biol. Chem. 276, 18863-18870 (2001).
110. Stacey, M. et al. EMR4, a novel epidermal growth factor (EGF)-TM7 molecule up-regulated in activated mouse macrophages, binds to a putative cellular ligand on B lymphoma cell line A20. J. Biol. Chem. 277, 29283-29293 (2002).
111. Hamann, J., Vogel, B., van Schijndel, G. M. & van Lier, R. A. The seven-span transmembrane receptor CD97 has a cellular ligand (CD55, DAF). J. Exp. Med. 184, 1185-1189 (1996).
112. Hamann, J. et al. Characterization of the CD55 (DAF)-binding site on the seven-span transmembrane receptor CD97. Eur. J. Immunol. 28, 1701-1707 (1998).
113. Xu, L., Begum, S., Hearn, J. D. & Hynes, R. O. GPR56, an atypical G protein-coupled receptor, binds tissue transglutaminase, TG2, and inhibits melanoma tumor growth and metastasis. Proc. Natl Acad. Sci. USA 103, 9023-9028 (2006).
114. Liu, M. et al. GPR56, a novel secretin-like human G-protein-coupled receptor gene. Genomics 55, 296-305 (1999).
115. Sugita, S., Ichtchenko, K., Khvotchev, M. & Sudhof, T. C. a-Latrotoxin receptor CIRL/latrophilin 1 (CL1) defines an unusual family of ubiquitous G-protein-linked receptors. G-protein coupling not required for triggering exocytosis. J. Biol. Chem. 273, 32715-32724 (1998).
116. Krasnoperov, V., Bittner, M. A., Holz, R. W., Chepurny, O. & Petrenko, A. G. Structural requirements for a-latrotoxin binding and a-latrotoxin-stimulated secretion. A study with calcium-independent receptor of a-latrotoxin (CIRL) deletion mutants. J. Biol. Chem. 274, 3590-3596 (1999).
117. Hadjantonakis, A. K. et al. Celsr1, a neural-specific gene encoding an unusual seven-pass transmembrane receptor, maps to mouse chromosome 15 and human chromosome 22qter. Genomics 45, 97-104 (1997).
118. Nakayama, M. et al. Identification of high-molecular- weight proteins with multiple EGF-like motifs by motif-trap screening. Genomics 51,27-34 (1998).
119. Usui, T. et al. Flamingo, a seven-pass transmembrane cadherin, regulates planar cell polarity under the control of Frizzled. Cell 98, 585-595 (1999).
120. Curtin, J. A. et al. Mutation of Celsr 1 disrupts planar polarity of inner ear hair cells and causes severe neural tube defects in the mouse. Curr. Biol. 13, 1129-1133 (2003).
121. Nishimori, H. et al. A novel brain-specific p53-target gene, BAI1, containing thrombospondin type 1 repeats inhibits experimental angiogenesis. Oncogene 15, 2145-2150 (1997).
122. Osterhoff, C., Ivell, R. & Kirchhoff, C. Cloning of a human epididymis-specific mRNA, HE6, encoding a novel member of the seven transmembrane-domain receptor superfamily. DNA Cell Biol. 16, 379-389 (1997).
123. Shiratsuchi, T., Nishimori, H., Ichise, H., Nakamura, Y. & Tokino, T. Cloning and characterization of BAI2 and BAI3, novel genes homologous to brain-specific angiogenesis inhibitor 1 (BAI1). Cytogenet. Cell Genet. 79, 103-108 (1997).
124. Nikkila, H. et al. Sequence similarities between a novel putative G protein-coupled receptor and Na+/Ca2 + exchangers define a cation binding domain. Mol. Endocrinol. 14, 1351-1364 (2000).
125. Fredriksson, R., Lagerstrom, M. C., Hoglund, P. J. & Schioth, H. B. Novel human G protein-coupled receptors with long N-terminals containing GPS domains and Ser/Thr-rich regions. FEBS Lett. 531, 407-414 (2002).
126. Fredriksson, R., Gloriam, D. E., Hoglund, P J., Lagerstrom, M. C. & Schioth, H. B. There exist at least 30 human G-protein-coupled receptors with long Ser/ Thr-rich N-termini. Biochem. Biophys. Res. Commun. 301, 725-734 (2003).
127. Lopezjimenez, N. D. et al. Two novel genes, Gpr113, which encodes a family 2 G-protein-coupled receptor, and Trcg1, are selectively expressed in taste receptor cells. Genomics 85, 472-482 (2005).
128. Abe, J., Suzuki, H., Notoya, M., Yamamoto, T. & Hirose, S. Ig-hepta, a novel member of the G proteincoupled hepta-helical receptor (GPCR) family that has immunoglobulin-like repeats in a long N-terminal extracellular domain and defines a new subfamily of GPCRs. J. Biol. Chem. 274, 19957-19964 (1999).
129. Abe, J., Fukuzawa, T. & Hirose, S. Cleavage of Ig-Hepta at a “SEA” module and at a conserved G proteincoupled receptor proteolytic site. J. Biol. Chem. 277, 23391-23398 (2002).
130. Wreschner, D. H. et al. Generation of ligand-receptor alliances by “SEA” module-mediated cleavage of membrane-associated mucin proteins. Protein Sci. 11, 698-706 (2002).
131. McMillan, D. R., Kayes-Wandover, K. M., Richardson, J. A. & White, P. C. Very large G protein-coupled receptor-1, the largest known cell surface protein, is highly expressed in the developing central nervous system. J. Biol. Chem. 277, 785-792 (2002).
132. McMillan, D. R. & White, P C. Loss of the transmembrane and cytoplasmic domains of the very large G-protein-coupled receptor-1 (VLGR1 or Mass1) causes audiogenic seizures in mice. Mol. Cell Neurosci. 26, 322-329 (2004).
133. Bjarnadottir, T. K. et al. Identification of novel splice variants of adhesion G protein-coupled receptors. Gene 387, 38-48 (2006).
134. Lagerstrom, M. C. et al. The evolutionary history and tissue mapping of GPR123: specific CNS expression pattern predominantly in thalamic nuclei and regions containing large pyramidal cells. J. Neurochem. 100, 1129-1142 (2007).
135. Bjarnadottir, T. K., Fredriksson, R. & Schioth, H. B. The gene repertoire and the common evolutionary history of glutamate, pheromone (V2R), taste(1) and other related G protein-coupled receptors. Gene 362, 70-84 (2005).
136. Kunishima, N. et al. Structural basis of glutamate recognition by a dimeric metabotropic glutamate receptor. Nature 407, 971-977 (2000).
137. O’Hara, P. J. et al. The ligand-binding domain in metabotropic glutamate receptors is related to bacterial periplasmic binding proteins. Neuron 11, 41-52 (1993).
138. Parmentier, M. L. et al. Conservation of the ligand recognition site of metabotropic glutamate receptors during evolution. Neuropharmacology 39, 1119-1131 (2000).
139. Muto T., Tsuchiya, D., Morikawa, K. & Jingami, H. Structures of the extracellular regions of the group II/ III metabotropic glutamate receptors. Proc. Natl Acad. Sci. USA 104, 3759-3764 (2007).
140. Brauner-Osborne, H., Jensen, A. A., Sheppard, P O., O’Hara, P. & Krogsgaard-Larsen, P. The agonist- binding domain of the calcium-sensing receptor is located at the amino-terminal domain. J. Biol. Chem. 274, 18382-18386 (1999).
141. Brown, E. M. et al. Cloning and characterization of an extracellular Ca2 + -sensing receptor from bovine parathyroid. Nature 366, 575-580 (1993).
142. Kuang, D. et al. Molecular similarities in the ligand binding pockets of an odorant receptor and the metabotropic glutamate receptors. J. Biol. Chem. 278, 42551-42559 (2003).
143. Wellendorph, P & Brauner-Osborne, H. Molecular cloning, expression, and sequence analysis of GPRC6A, a novel family C G-protein-coupled receptor. Gene 335, 37-46 (2004).
144. Silve, C. et al. Delineating a Ca2 + binding pocket within the venus flytrap module of the human calcium- sensing receptor. J. Biol. Chem. 280, 37917-37923 (2005).
145. Hermans, E. & Challiss, R. A. Structural, signalling and regulatory properties of the group I metabotropic glutamate receptors: prototypic family C G-protein-coupled receptors. Biochem. J. 359, 465-484 (2001).
146. Nakanishi, S. Molecular diversity of glutamate receptors and implications for brain function. Science 258, 597-603 (1992).
147. Kubo, Y., Miyashita, T. & Murata, Y. Structural basis for a Ca2+-sensing function of the metabotropic glutamate receptors. Science 279, 1722-1725 (1998).
148. Conigrave, A. D., Quinn, S. J. & Brown, E. M. L-Amino acid sensing by the extracellular Ca2+-sensing receptor. Proc. Natl Acad. Sci. USA 97, 4814-4819 (2000).
149. Xu, H. et al. Different functional roles of T1R subunits in the heteromeric taste receptors. Proc. Natl Acad. Sci. USA 101, 14258-14263 (2004).
150. Rondard, P et al. Coupling of agonist binding to effector domain activation in metabotropic glutamate- like receptors. J. Biol. Chem. 281, 24653-24661 (2006).
151. Yu, L. et al. NCD3G: a novel nine-cysteine domain in family 3 GPCRs. Trends Biochem. Sci. 29, 458-461 (2004).
152. Hu, J., Hauache, O. & Spiegel, A. M. Human Ca2 + receptor cysteine-rich domain. Analysis of function of mutant and chimeric receptors. J. Biol. Chem. 275, 16382-16389 (2000).
153. Tan, Y. M. et al. Autosomal dominant hypocalcemia: a novel activating mutation (E604K) in the cysteine- rich domain of the calcium-sensing receptor. J. Clin. Endocrinol. Metab. 88, 605-610 (2003).
154. Jiang, P et al. The cysteine-rich region of T1R3 determines responses to intensely sweet proteins. J. Biol. Chem. 279, 45068-45075 (2004).
155. Kaupmann, K. et al. Expression cloning of GABAb receptors uncovers similarity to metabotropic glutamate receptors. Nature 386, 239-246 (1997).
156. Martin, S. C., Russek, S. J. & Farb, D. H. Human GABAbR genomic structure: evidence for splice variants in GABAbRI but not GABAbR2. Gene 278, 63-79 (2001).
157. Galvez, T. et al. Mutagenesis and modeling of the GABAb receptor extracellular domain support a venus flytrap mechanism for ligand binding. J. Biol. Chem. 274, 13362-13369 (1999).
158. Reid, K. B. & Day, A. J. Structure-function relationships of the complement components. Immunol. Today 10, 177-180 (1989).
159. Ichinose, A., Bottenus, R. E. & Davie, E. W. Structure of transglutaminases. J. Biol. Chem. 265, 13411-13414 (1990).
160. Liu, J. et al. Molecular determinants involved in the allosteric control of agonist affinity in the GABAb receptor by the GABAb-, subunit. J. Biol. Chem. 279, 15824-15830 (2004).
161. Kniazeff, J. et al. Locking the dimeric GABAb G-protein-coupled receptor in its active state. J. Neurosci. 24, 370-377 (2004).
162. Shoback, D. M. et al. The calcimimetic cinacalcet normalizes serum calcium in subjects with primary hyperparathyroidism. J. Clin. Endocrinol. Metab. 88, 5644-5649 (2003).
163. Malherbe, P. et al. Mutational analysis and molecular modeling of the binding pocket of the metabotropic glutamate 5 receptor negative modulator 2-methyl-6-(phenylethynyl)-pyridine. Mol. Pharmacol. 64, 823-832 (2003).
164. Litschig, S. et al. CPCCOEt, a noncompetitive metabotropic glutamate receptor 1 antagonist, inhibits receptor signaling without affecting glutamate binding. Mol. Pharmacol. 55, 453-461 (1999).
165. Gasparini, F., Kuhn, R. & Pin, J. P. Allosteric modulators of group I metabotropic glutamate receptors: novel subtype-selective ligands and therapeutic perspectives. Curr. Opin. Pharmacol. 2, 43-49 (2002).
166. Petrel, C. et al. Positive and negative allosteric modulators of the Ca+-sensing receptor interact within overlapping but not identical binding sites in the transmembrane domain. J. Biol. Chem. 279, 18990-18997 (2004).
167. Petrel, C. et al. Modeling and mutagenesis of the binding site of Calhex 231, a novel negative allosteric modulator of the extracellular Ca + -sensing receptor. J. Biol. Chem. 278, 49487-49494 (2003).
168. Knoflach, F. et al. Positive allosteric modulators of metabotropic glutamate 1 receptor: characterization, mechanism of action, and binding site. Proc. Natl Acad. Sci. USA 98, 13402-13407 (2001).
169. Jiang, P. et al. Identification of the cyclamate interaction site within the transmembrane domain of the human sweet taste receptor subunit T1R3. J. Biol. Chem. 280, 34296-34305 (2005).
170. Jiang, P. et al. Lactisole interacts with the transmembrane domains of human T1R3 to inhibit sweet taste. J. Biol. Chem. 280, 15238-15246 (2005).
171. Binet, V. et al. The heptahelical domain of GABAb- is activated directly by CGP7930, a positive allosteric modulator of the GABAb receptor. J. Biol. Chem. 279, 29085-29091 (2004).
172. Chen, Y. et al. Interaction of novel positive allosteric modulators of metabotropic glutamate receptor 5 with the negative allosteric antagonist site is required for potentiation of receptor responses. Mol. Pharmacol. 71, 1389-1398 (2007).
173. Wellendorph, P. et al. Deorphanization of GPRC6A: a promiscuous L-a-amino acid receptor with preference for basic amino acids. Mol. Pharmacol. 67, 589-597 (2005).
174. Christiansen, B., Hansen, K. B., Wellendorph, P. & Brauner-Osborne, H. Pharmacological characterization of mouse GPRC6A, an L-a--amino-acid receptor modulated by divalent cations. Br. J. Pharmacol. 150, 798-807 (2007).
175. Calver, A. R. et al. Molecular cloning and characterisation of a novel GABAB-related G-protein coupled receptor. Brain Res. Mol. Brain Res. 110, 305-317 (2003).
176. Cheng, Y. & Lotan, R. Molecular cloning and characterization of a novel retinoic acid-inducible gene that encodes a putative G protein-coupled receptor. J. Biol. Chem. 273, 35008-35015 (1998).
177. Brauner-Osborne, H. et al. Cloning and characterization of a human orphan family C G-protein coupled receptor GPRC5D. Biochim. Biophys. Acta 1518, 237-248 (2001).
178. Brauner-Osborne, H. & Krogsgaard-Larsen, P. Sequence and expression pattern of a novel human orphan G-protein-coupled receptor, GPRC5B, a family C receptor with a short amino-terminal domain. Genomics 65, 121-128 (2000).
179. Robbins, M. J. et al. Molecular cloning and characterization of two novel retinoic acid-inducible orphan G-protein-coupled receptors (GPRC5B and GPRC5C). Genomics 67, 8-18 (2000).
180. Ota, T. et al. Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature Genet. 36, 40-45 (2004).
181. Vinson, C. R., Conover, S. & Adler, P N. A Drosophila tissue polarity locus encodes a protein containing seven potential transmembrane domains. Nature 338, 263-264 (1989).
182. Wang, Y. et al. A large family of putative transmembrane receptors homologous to the product of the Drosophila tissue polarity gene frizzled. J. Biol. Chem. 271,4468-4476 (1996).
183. Wang, Y. K. et al. A novel human homologue of the Drosophila frizzled wnt receptor gene binds wingless protein and is in the Williams syndrome deletion at 7q11.23. Hum. Mol. Genet. 6, 465-472 (1997).
184. Zhao, Z., Lee, C. C., Baldini, A. & Caskey, C. T. A human homologue of the Drosophila polarity gene frizzled has been identified and mapped to 17q21.1. Genomics 27, 370-373 (1995).
185. Tokuhara, M., Hirai, M., Atomi, Y., Terada, M. & Katoh, M. Molecular cloning of human Frizzled-6. Biochem. Biophys. Res. Commun. 243, 622-627(1998).
186. Sala, C. F., Formenti, E., Terstappen, G. C. & Caricasole, A. Identification, gene structure, and expression of human frizzled-3 (FZD3). Biochem. Biophys. Res. Commun. 273, 27-34 (2000).
187. Sagara, N., Toda, G., Hirai, M., Terada, M. & Katoh, M. Molecular cloning, differential expression, and chromosomal localization of human frizzled-1, frizzled-2, and frizzled-7. Biochem. Biophys. Res. Commun. 252, 117-122 (1998).
188. Saitoh, T., Hirai, M. & Katoh, M. Molecular cloning and characterization of human Frizzled-8 gene on chromosome 10p 11.2. Int. J. Oncol. 18, 991-996 (2001).
189. Kirikoshi, H. et al. Molecular cloning and characterization of human Frizzled-4 on chromosome 11q14-q21. Biochem. Biophys. Res. Commun. 264, 955-961 (1999).
190. Koike, J. et al. Molecular cloning of Frizzled-10, a novel member of the Frizzled gene family. Biochem. Biophys. Res. Commun. 262, 39-43 (1999).
191. Bhanot, P. et al. A new member of the frizzled family from Drosophila functions as a Wingless receptor. Nature 382, 225-230 (1996).
192. Murone, M., Rosenthal, A. & de Sauvage, F. J. Sonic hedgehog signaling by the patched-smoothened receptor complex. Curr. Biol. 9, 76-84 (1999).
193. Slusarski, D. C., Corces, V. G. & Moon, R. T. Interaction of Wnt and a Frizzled homologue triggers G-protein-linked phosphatidylinositol signalling. Nature 390, 410-413 (1997).
194. Riobo, N. A., Saucy, B., Dilizio, C. & Manning, D. R. Activation of heterotrimeric G proteins by Smoothened. Proc. NatlAcad. Sci. USA 103, 12607-12612 (2006).
195. Barnes, M. R., Duckworth, D. M. & Beeley, L. J. Frizzled proteins constitute a novel family of G protein-coupled receptors, most closely related to the secretin family. Trends Pharmacol. Sci. 19, 399-400 (1998).
196. Carron, C. et al. Frizzled receptor dimerization is sufficient to activate the Wnt/ß-catenin pathway. J. Cell Sci. 116, 2541-2550 (2003).
197. Dann, C. E. et al. Insights into Wnt binding and signalling from the structures of two Frizzled cysteine-rich domains. Nature 412, 86-90 (2001).
198. Chen, C. M., Strapps, W., Tomlinson, A. & Struhl, G. Evidence that the cysteine-rich domain of Drosophila Frizzled family receptors is dispensable for transducing Wingless. Proc. Natl Acad. Sci. USA 101, 15961-15966 (2004).
199. Xu, Q. et al. Vascular development in the retina and inner ear: control by Norrin and Frizzled-4, a high- affinity ligand-receptor pair. Cell 116, 883-895 (2004).
200. Robitaille, J. et al. Mutant frizzled-4 disrupts retinal angiogenesis in familial exudative vitreoretinopathy. Nature Genet. 32, 326-330 (2002).
201. Fritze, O. et al. Role of the conserved NPxxY(x)5, 6F motif in the rhodopsin ground state and during activation. Proc. Natl Acad. Sci. USA 100, 2290-2295 (2003).
202. Stone, D. M. et al. The tumour-suppressor gene patched encodes a candidate receptor for Sonic hedgehog. Nature 384, 129-134 (1996).
203. Nakano, Y. et al. Functional domains and sub-cellular distribution of the Hedgehog transducing protein Smoothened in Drosophila. Mech. Dev. 121,507-518 (2004).
204. Chen, Y. & Struhl, G. In vivo evidence that Patched and Smoothened constitute distinct binding and transducing components of a Hedgehog receptor complex. Development 125, 4943-4948 (1998).
205. Taipale, J. et al. Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine. Nature 406, 1005-1009 (2000).
206. Chen, J. K., Taipale, J., Young, K. E., Maiti, T. & Beachy, P. A. Small molecule modulation of Smoothened activity. Proc. Natl Acad. Sci. USA 99, 14071-14076 (2002).
207. Frank-Kamenetsky, M. et al. Small-molecule modulators of Hedgehog signaling: identification and characterization of Smoothened agonists and antagonists. J. Biol. 1, 10 (2002).
208. Nagayama, S. et al. Therapeutic potential of antibodies against FZD 10, a cell-surface protein, for synovial sarcomas. Oncogene 24, 6201-6212 (2005).
209. Shi, P., Zhang, J., Yang, H. & Zhang, Y. P Adaptive diversification of bitter taste receptor genes in mammalian evolution. Mol. Biol. Evol. 20, 805-814 (2003).
210. Go, Y., Satta, Y., Takenaka, O. & Takahata, N. Lineage-specific loss of function of bitter taste receptor genes in humans and nonhuman primates. Genetics 170, 313-326 (2005).
211. Conte, C., Ebeling, M., Marcuz, A., Nef, P & Andres- Barquin, P. J. Identification and characterization of human taste receptor genes belonging to the TAS2R family. Cytogenet. Genome Res. 98, 45-53 (2002).
212. Bufe, B., Hofmann, T., Krautwurst, D., Raguse, J. D. & Meyerhof, W. The human TAS2R16 receptor mediates bitter taste in response to ß-glucopyranosides. Nature Genet. 32, 397-401 (2002).
213. Chandrashekar, J. et al. T2Rs function as bitter taste receptors. Cell 100, 703-711 (2000).
214. Behrens, M. et al. The human taste receptor hTAS2R14 responds to a variety of different bitter compounds. Biochem. Biophys. Res. Commun. 319, 479-485 (2004).
215. Kuhn, C. et al. Bitter taste receptors for saccharin and acesulfame K. J. Neurosci. 24, 10260-10265 (2004).
216. Ueda, T. et al. Identification of coding single-nucleotide polymorphisms in human taste receptor genes involving bitter tasting. Biochem. Biophys. Res. Commun. 285, 147-151 (2001).
217. Pronin, A. N., Tang, H., Connor, J. & Keung, W. Identification of ligands for two human bitter T2R receptors. Chem. Senses 29, 583-593 (2004).
218. Gloriam, D. E. et al. The repertoire of trace amine G-protein-coupled receptors: large expansion in zebrafish. Mol. Phylogenet Evol. 35, 470-482 (2005).
219. Kostenis, E. A glance at G-protein-coupled receptors for lipid mediators: a growing receptor family with remarkably diverse ligands. Pharmacol. Ther. 102, 243-257 (2004).
220. Cavalier-Smith, T. Only six kingdoms of life. Proc. Biol. Sci. 271, 1251-1262 (2004).
221. Pupillo, M., Insall, R., Pitt, G. S. & Devreotes, P. N. Multiple cyclic AMP receptors are linked to adenylyl cyclase in Dictyostelium. Mol. Biol. Cell 3, 1229-1234 (1992).
222. Blumer, K. J. & Thorner, J. ß and y subunits of a yeast guanine nucleotide-binding protein are not essential for membrane association of the a subunit but are required for receptor coupling. Proc. Natl Acad. Sci. USA 87, 4363-4367 (1990).
223. Xue, Y. Batlle M. & Hirsch, J. P. GPR1 encodes a putative G protein-coupled receptor that associates with the Gpa2p Ga subunit and functions in a Ras-independent pathway. EMBO J. 17, 1996-2007 (1998).
224. Prabhu, Y. & Eichinger, L. The Dictyostelium repertoire of seven transmembrane domain receptors. Eur. J. Cell Biol. 85, 937-946 (2006).
225. Williams, J. G., Noegel, A. A. & Eichinger, L. Manifestations of multicellularity: Dictyostelium reports in. Trends Genet. 21,392-398 (2005).
226. Perez, D. M. From plants to man: the GpCR “tree of life”. Mol. Pharmacol. 67, 1383-1384 (2005).
227. Perez, D. M. The evolutionarily triumphant G-protein-coupled receptor. Mol. Pharmacol. 63, 1202-1205 (2003).
228. Parameswaran, N. & Spielman, W. S. RAMPs: the past, present and future. Trends Biochem. Sci. 31, 631-638 (2006).
229. Gurevich, E. V. & Gurevich, V. V. Arrestins: ubiquitous regulators of cellular signaling pathways. Genome Biol. 7, 236 (2006).
230. McCudden, C. R., Hains, M. D., Kimple, R. J., Siderovski, D. P & Willard, F. S. G-protein signaling: back to the future. Cell. Mol. Life Sci. 62, 551-577 (2005).
231. Whitehead, I. P., Zohn, I. E. & Der, C. J. Rho GTPase- dependent transformation by G protein-coupled receptors. Oncogene 20, 1547-1555 (2001).
232. Shi, P. & Zhang, J. Contrasting modes of evolution between vertebrate sweet/umami receptor genes and bitter receptor genes. Mol. Biol. Evol. 23, 292-300 (2005).
233. Thompson, J. D., Higgins, D. G. & Gibson, T. J. CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. Nucleic Acids Res. 22, 4673-4680 (1994).
234. Donnelly, D. The arrangement of the transmembrane helices in the secretin receptor family of G-protein- coupled receptors. FEBS Lett. 409, 431-436 (1997).
235. Couvineau, A. etal. Highly conserved aspartate 68, tryptophane 73 and glycine 109 in the N-terminal extracellular domain of the human VIP receptor are essential for its ability to bind VIP. Biochem. Biophys. Res. Commun. 206, 246-252 (1995).
236. Carruthers, C. J., Unson, C. G., Kim, H. N. & Sakmar, T. P Synthesis and expression of a gene for the rat glucagon receptor. Replacement of an aspartic acid in the extracellular domain prevents glucagon binding. J. Biol. Chem. 269, 29321-29328 (1994).
237. Holtmann, M. H., Ganguli, S., Hadac, E. M., Dolu, V. & Miller, L. J. Multiple extracellular loop domains contribute critical determinants for agonist binding and activation of the secretin receptor. J. Biol. Chem. 271, 14944-14949 (1996).
238. Bisello, A. et al. Parathyroid hormone-receptor interactions identified directly by photocross-linking and molecular modeling studies. J. Biol. Chem. 273, 22498-22505 (1998).
239. Di Paolo, E. et al. Role of charged amino acids conserved in the vasoactive intestinal polypeptide/ secretin family of receptors on the secretin receptor functionality. Peptides 20, 1187-1193 (1999).
240. Zhou, A. T. et al. Direct mapping of an agonist- binding domain within the parathyroid hormone/ parathyroid hormone-related protein receptor by photoaffinity crosslinking. Proc. Natl Acad. Sci. USA 94, 3644-3649 (1997).
241. Sydow, S., Flaccus, A., Fischer, A. & Spiess, J. The role of the fourth extracellular domain of the rat corticotropin-releasing factor receptor type 1 in ligand binding. Eur. J. Biochem. 259, 55-62 (1999).
242. Piserchio, A., Bisello, A., Rosenblatt, M., Chorev, M. & Mierke, D. F. Characterization of parathyroid hormone/ receptor interactions: structure of the first extracellular loop. Biochemistry 39, 8153-8160 (2000).
243. Solano, R. M. et al. Two basic residues of the h-VPAC 1 receptor second transmembrane helix are essential for ligand binding and signal transduction. J. Biol. Chem. 276, 1084-1088 (2001).
244. Runge, S. et al. Three distinct epitopes on the extracellular face of the glucagon receptor determine specificity for the glucagon amino terminus. J. Biol. Chem. 278, 28005-28010 (2003).
245. Lins, L. et al. The human VPAC1 receptor: three- dimensional model and mutagenesis of the N-terminal domain. J. Biol. Chem. 276, 10153-10160 (2001).
246. Langer, I., Vertongen, P., Perret, J., Waelbroeck, M. & Robberecht, P. Lysine 195 and aspartate 196 in the first extracellular loop of the VPAC1 receptor are essential for high affinity binding of agonists but not of antagonists. Neuropharmacology 44, 125-131 (2003).
247. Marchler-Bauer, A. et al. CDD: a Conserved Domain Database for protein classification. Nucleic Acids Res. 33, D192-D196 (2005).
248. Lin, H. H., Stacey, M., Hamann, J., Gordon, S. & McKnight, A. J. Human EMR2, a novel EGF-TM7 molecule on chromosome 19p 13.1, is closely related to CD97. Genomics 67, 188-200 (2000).
249. Zhang, Z. et al. Three adjacent serines in the extracellular domains of the CaR are required for L-amino acid-mediated potentiation of receptor function. J. Biol. Chem. 277, 33727-33735 (2002).
250. Galvez, T. et al. Mapping the agonist-binding site of GABAB type 1 subunit sheds light on the activation process of GABAB receptors. J. Biol. Chem. 275, 41166-41174 (2000).
251. Laurie, D. J., Schoeffter, P, Wiederhold, K. H. & Sommer, B. Cloning, distribution and functional expression of the human mGlu6 metabotropic glutamate receptor. Neuropharmacology 36, 145-152 (1997).
252. Hendy, G. N., D'Souza-Li, L., Yang, B., Canaff, L. & Cole, D. E. Mutations of the calcium-sensing receptor (CASR) in familial hypocalciuric hypercalcemia, neonatal severe hyperparathyroidism, and autosomal dominant hypocalcemia. Hum. Mutat. 16, 281-296 (2000).
253. Fatkenheuer G. et al. Efficacy of short-term monotherapy with maraviroc, a new CCR5 antagonist, in patients infected with HIV-1. Nature Med. 11, 1170-1172 (2005).